Background: Chromium is an essential nutrient for the maintenance of normal glucose tolerance. While studies of chromium supplementation in patients with type 2 diabetes (T2D) have indicated that this agent lowers glucose and insulin levels, its cellular mechanism of action is not welt understood. Studies both in humans and in cell culture suggest that chromium enhances the insulin signaling pathway. We propose, therefore, to study chromium's effects on insulin-stimulated glucose uptake in a well characterized population of non-obese, non-diabetic subjects with insulin resistantance. This population is ideal for an analysis of the effects of chromium on insulin action, because they are as insulin resistant as T2D patients but do not have the important confounder of hyperglycemia. Because these insulin resistant subjects are at risk for the development of T2D, the Metabolic Syndrome, and coronary artery disease (CAD), a demonstration of the beneficial effects of chromium on insulin action could ultimately have important public health consequences. Hypotheses: (1) Chromium will improve insulin sensitivity in a general population of non-obese, insulin-resistant, non-diabetic subjects; and (2) The improvement of insulin action by chromium is due to its effects on the major components of the insulin signling pathway (insulin receptor, IRS proteins, PI 3-kinase, PKB/AKT and GLUT4); and/ or regulators of the insulin signaling pathway (PTP 1B, PC-1, IKK, NF-KappaB and PKC) Methods: The insulin sensitivity of 180 subjects will be initially estimated by homeostasis model assessment. The most insulin resistant subjects will then be randomized to 16 weeks of therapy with either chromium or placebo. To quantitate chromium-induced improvements in both in insulin sensitivity and the insulin signaling pathway, euglycemic hyperinsulinemic clamps with muscle biopsies will be performed before and after treament. Anticipated Results and Significance: We believe these studies will (1) confirm the beneficial effect of chromium on insulin sensitvity; (2) further our understanding of the molecular mechanisms of chromium action; and (3) form a basis for a larger project examining the long term efficacy of chromium in preventing the developement of T2D and CAD.